International Journal of Oral Biology

The Korean Academy of Oral Biology (대한구강생물학회)
권호 표지
DOI QR코드

DOI QR Code

Stemness and Proliferation of Murine Skin-Derived Precursor Cells under Hypoxic Environment

  • Kim, Hyewon (Cellular Reprogramming and Embryo Biotechnology Lab, BK21 and Dental Research Institute, Seoul National University School of Dentistry) ;
  • Park, Sangkyu (Cellular Reprogramming and Embryo Biotechnology Lab, BK21 and Dental Research Institute, Seoul National University School of Dentistry) ;
  • Roh, Sangho (Cellular Reprogramming and Embryo Biotechnology Lab, BK21 and Dental Research Institute, Seoul National University School of Dentistry)
  • Received : 2016.05.18
  • Accepted : 2016.06.05
  • Published : 2016.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Skin-derived precursors (SKPs) have potential to differentiate to various cell types including osteoblasts, adipocytes and neurons. SKPs are a candidate for cell-based therapy since they are easily accessible and have multipotency. Most mammalian cells are exposed to a low oxygen environment with 1 to 5% $O_2$ concentration in vivo, while 21% $O_2$ concentration is common in in vitro culture. The difference between in vitro and in vivo $O_2$ concentration may affect to the behavior of cultured cells. In this report, we investigated the effect of hypoxic condition on stemness and proliferation of SKPs. The results indicated that SKPs exposed to hypoxic condition for 5 days showed no change in proliferation. In terms of mRNA expression, hypoxia maintained expression of stemness markers; whereas, oncogenes, such as Klf4 and c-Myc, were downregulated, and the expression of Nestin, related to cancer migration, was also downregulated. Thus, SKPs cultured in hypoxia may reduce the risk of cancer in SKP cell-based therapy.

Keywords

References

  1. Biernaskie JA, McKenzie IA, Toma JG, Miller FD. Isolation of skin-derived precursors (SKPs) and differentiation and enrichment of their Schwann cell progeny. Nat Protoc. 2006;1:2803-2812. doi:10.1038/nprot.2006.422.
  2. Toma JG, Akhavan M, Fernandes KJ, Barnabe-Heider F, Sadikot A, Kaplan DR, Miller FD. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 2001;3:778-784. doi:10.1038/ncb0901-778.
  3. Kim JA, Ha S, Shin KY, Kim S, Lee KJ, Chong YH, Chang KA, Suh YH. Neural stem cell transplantation at critical period improves learning and memory through restoring synaptic impairment in Alzheimer's disease mouse model. Cell Death Dis. 2015;6:e1789. doi:10.1038/cddis.2015.138.
  4. Kim SU, Lee HJ, Kim YB. Neural stem cell-based treatment for neurodegenerative diseases. Neuropathology. 2013;33: 491-504. doi:10.1111/neup.12020.
  5. Xu S, Liu H, Xie Y, Sang L, Liu J, Chen B. Effect of mesenchymal stromal cells for articular cartilage degeneration treatment: a meta-analysis. Cytotherapy. 2015;17:1342-1352. doi:10.1016/j.jcyt.2015.05.005.
  6. Ho MS, Mei SH, Stewart DJ. The Immunomodulatory and Therapeutic Effects of Mesenchymal Stromal Cells for Acute Lung Injury and Sepsis. J Cell Physiol. 2015;230:2606-2617. doi:10.1002/jcp.25028.
  7. Tunici P, Bulte JW, Bruzzone MG, Poliani PL, Cajola L, Grisoli M, Douglas T, Finocchiaro G. Brain engraftment and therapeutic potential of stem/progenitor cells derived from mouse skin. J Gene Med. 2006;8:506-513. doi:10.1002/jgm.866.
  8. Kwok CK, Tam PK, Ngan ES. Potential use of skin-derived precursors (SKPs) in establishing a cell-based treatment model for Hirschsprung's disease. J Pediatr Surg. 2013;48:619-628. doi:10.1016/j.jpedsurg.2012.08.026.
  9. Mao D, Yao X, Feng G, Yang X, Mao L, Wang X, Ke T, Che Y, Kong D. Skin-derived precursor cells promote angiogenesis and stimulate proliferation of endogenous neural stem cells after cerebral infarction. Biomed Res Int. 2015;2015:945846. doi:10.1155/2015/945846.
  10. Liu Y, Chen J, Liu W, Lu X, Liu Z, Zhao X, Li G, Chen Z. A Modified Approach to Inducing Bone Marrow Stromal Cells to Differentiate into Cells with Mature Schwann Cell Phenotypes. Stem Cells Dev. 2016;25:347-359. doi:10.1089/scd.2015.0295.
  11. Santilli G, Lamorte G, Carlessi L, Ferrari D, Rota Nodari L, Binda E, Delia D, Vescovi AL, De Filippis L. Mild hypoxia enhances proliferation and multipotency of human neural stem cells. PLoS One. 2010;5:e8575. doi:10.1371/journal.pone.0008575.
  12. Braunschweig L, Meyer AK, Wagenfuhr L, Storch A. Oxygen regulates proliferation of neural stem cells through Wnt/ beta-catenin signalling. Mol Cell Neurosci. 2015; 67:84-92. doi:10.1016/j.mcn.2015.06.006.
  13. Chen HC, Sytwu HK, Chang JL, Wang HW, Chen HK, Kang BH, Liu DW, Chen CH, Chao TT, Wang CH. Hypoxia enhances the stemness markers of cochlear stem/progenitor cells and expands sphere formation through activation of hypoxiainducible factor-1 alpha. Hear Res. 2011;275:43-52. doi:10.1016/j.heares.2010.12.004.
  14. Fernandes KJ, McKenzie IA, Mill P, Smith KM, Akhavan M, Barnabe-Heider F, Biernaskie J, Junek A, Kobayashi NR, Toma JG, Kaplan DR, Labosky PA, Rafuse V, Hui CC, Miller FD. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol. 2004;6:1082-1093. doi:10.1038/ncb1181.
  15. Fernandes KJ, Kobayashi NR, Gallagher CJ, Barnabe-Heider F, Aumont A, Kaplan DR, Miller FD. Analysis of the neurogenic potential of multipotent skin-derived precursors. Exp Neurol. 2006;201:32-48. doi:10.1016/j.expneurol.2006.03.018.
  16. Lorenz K, Sicker M, Schmelzer E, Rupf T, Salvetter J, Schulz-Siegmund M, Bader A. Multilineage differentiation potential of human dermal skin-derived fibroblasts. Exp Dermatol. 2008;17:925-932. doi:10.1111/j.1600-0625.2008.00724.x.
  17. Csete M. Oxygen in the cultivation of stem cells. Ann N Y Acad Sci. 2005;1049:1-8. doi:10.1196/annals.1334.001.
  18. Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 2010;7:150-161. doi:10.1016/j.stem.2010.07.007.
  19. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell. 2005;9:617-628. doi:10.1016/j.devcel.2005.09.010.
  20. Beegle J, Lakatos K, Kalomoiris S, Stewart H, Isseroff RR, Nolta JA, Fierro FA. Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo. Stem Cells. 2015;33:1818-1828. doi:10.1002/stem.1976.
  21. Yoshida Y, Takahashi K, Okita K, Ichisaka T, Yamanaka S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell. 2009;5:237-241. doi:10.1016/j.stem.2009.08.001.
  22. Holzwarth C, Vaegler M, Gieseke F, Pfister SM, Handgretinger R, Kerst G, Muller I. Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells. BMC Cell Biol. 2010;11:11. doi:10.1186/1471-2121-11-11.
  23. Tamama K, Kawasaki H, Kerpedjieva SS, Guan J, Ganju RK, Sen CK. Differential roles of hypoxia inducible factor subunits in multipotential stromal cells under hypoxic condition. J Cell Biochem. 2011;112:804-817. doi:10.1002/jcb.22961.
  24. Bruick RK. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev. 2003;17:2614-2623. doi:10.1101/gad.1145503.
  25. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG, Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464-468. doi:10.1126/science.1059817.
  26. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292: 468-472. doi:10.1126/science.1059796.
  27. Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE. 2005;2005:re12. doi:10.1126/stke.3062005re12.
  28. Shi YAi W. Function of KLF4 in Stem Cell Biology. 2013. doi:10.5772/54370.
  29. Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. c-Myc and cancer metabolism. Clin Cancer Res. 2012;18:5546-5553. doi:10.1158/1078-0432.CCR-12-0977.
  30. Yu F, Shi Y, Wang J, Li J, Fan D, Ai W. Deficiency of Kruppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells. Int J Cancer. 2013;133:2872-2883. doi:10.1002/ijc.28302.
  31. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11:335-347. doi:10.1016/j.ccr.2007.02.006.
  32. Chen Z, Wang J, Cai L, Zhong B, Luo H, Hao Y, Yu W, Wang B, Su C, Lei Y, Bella AE, Xiang AP, Wang T. Role of the stem cell-associated intermediate filament nestin in malignant proliferation of non-small cell lung cancer. PLoS One. 2014;9:e85584. doi:10.1371/journal.pone.0085584.
  33. Zhao Z, Lu P, Zhang H, Xu H, Gao N, Li M, Liu C. Nestin positively regulates the Wnt/beta-catenin pathway and the proliferation, survival and invasiveness of breast cancer stem cells. Breast Cancer Res. 2014;16:408. doi:10.1186/s13058-014-0408-8.
  34. Hyder CL, Lazaro G, Pylvanainen JW, Roberts MW, Qvarnstrom SM, Eriksson JE. Nestin regulates prostate cancer cell invasion by influencing the localisation and functions of FAK and integrins. J Cell Sci. 2014;127:2161-2173. doi:10.1242/jcs.125062.
  35. Matsuda Y. The Roles and Molecular Mechanisms of Nestin Expression in Cancer with a Focus on Pancreatic Cancer. Journal of Carcinogenesis & Mutagenesis. 2013;01. doi:10.4172/2157-2518.s9-002.
  36. Ehrmann J, Kolar Z, Mokry J. Nestin as a diagnostic and prognostic marker: immunohistochemical analysis of its expression in different tumours. J Clin Pathol. 2005;58: 222-223. doi:10.1136/jcp.2004.021238.
  37. Narita K, Matsuda Y, Seike M, Naito Z, Gemma A, Ishiwata T. Nestin regulates proliferation, migration, invasion and stemness of lung adenocarcinoma. Int J Oncol. 2014;44: 1118-1130. doi:10.3892/ijo.2014.2278.
  38. Cairns RAHill RP. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma. Cancer Res. 2004;64:2054-2061. https://doi.org/10.1158/0008-5472.CAN-03-3196
  39. Yu LHales CA. Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice. BMC Cancer. 2011;11:331. doi:10.1186/1471-2407-11-331.
  40. Yu X, Lu C, Liu H, Rao S, Cai J, Liu S, Kriegel AJ, Greene AS, Liang M, Ding X. Hypoxic preconditioning with cobalt of bone marrow mesenchymal stem cells improves cell migration and enhances therapy for treatment of ischemic acute kidney injury. PLoS One. 2013;8:e62703. doi:10.1371/journal.pone.0062703.